This K24 application has supported my career development in patient oriented research and mentoring. The original grant focused on clinical studies using new agents which putatively target epigenetically-mediated aberrant gene transcription in cancer. These included a Phase I study of a novel combination of the DNA methyltransferase inhibitor 5-azacytidine (5AC) with an oral histone deacetylase (HDAC) inhibitor entinostat in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML);a randomized Phase II trial of two schedules of the HDAC inhibitor vorinostat in patients with relapsed or high risk AML;and a national US Leukemia Intergroup randomized Phase II trial (E1905) comparing the 5AC/entinostat combination to 5AC alone for the treatment of MDS, chronic myelomonocytic leukemia, and AML with trilineage dysplasia (MDS-associated, AML-TLD). Together with intensive correlative laboratory science aimed at dissecting the mechanisms by which these "epigenetically targeted" drugs exert their clinical activity, these studies have been fertile ground for intensive mentoring of pre- and post-doctoral trainees in biologically-driven drug development. This renewal application requests an additional five years of funding to continue my development in patient oriented research and mentoring as I continue to build integrated programs in epigenetically targeted drug development in hematologic malignancies at Johns Hopkins and nationally, and increase my abilities and reach as a mentor to more junior faculty at Hopkins and at other institutions. The research in which mentees will be involved includes the correlative science associated with E1905, which is the first major trial to critically assess the clinical benefit of the addition of an HDAC inhibitor to a DNA methyltransferase inhibitor. These combinations have been developed based on in vitro data demonstrating synergistic re-expression of genes silenced through methylation of cytosines in gene promoters. The correlative studies focus on identifying alterations and signatures in the DNA methylome upon treatment, which correlate with clinical response to 5AC/entinostat. The second aim will compare clinical outcomes when entinostat is given in a sequential manner (following 5AC) rather than the current overlapping schedule. The third aim will examine to what extent epigenetic modifications differ when the HDAC inhibitor is given concomitantly with the DNMT inhibitor versus sequential administration PUBLIC HEALTH RELEVANCE: Drugs which target aberrant transcription in cancer through modification of epigenetic marks demonstrate marked activity in myeloid leukemias;however the mechanism by which these drugs improve clinical outcome remains uncertain. Understanding the mechanism underlying clinically activity is critical for development of better drugs, and for the effective development of epigenetically-targeted strategies in other more common cancers.